Submissions for variant NM_019892.6(INPP5E):c.1456C>T (p.Arg486Cys)

gnomAD frequency: 0.00004  dbSNP: rs75939033

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420326	SCV000534823	uncertain significance	not provided	2016-12-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the INPP5E gene. The R486C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R486C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R486C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001239212	SCV001412067	pathogenic	Familial aplasia of the vermis	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 486 of the INPP5E protein (p.Arg486Cys). This variant is present in population databases (rs75939033, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 34188062; Invitae). ClinVar contains an entry for this variant (Variation ID: 391693). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt INPP5E protein function. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376303	SCV001573397	likely pathogenic	Rod-cone dystrophy	2021-04-08	criteria provided, single submitter	research	The INPP5E c.1456C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PP3, PP1. Based on this evidence we have classified this variant as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003401434	SCV004110266	uncertain significance	INPP5E-related condition	2023-11-29	criteria provided, single submitter	clinical testing	The INPP5E c.1456C>T variant is predicted to result in the amino acid substitution p.Arg486Cys. This variant has been reported in two unrelated individuals with rod-cone degeneration and a patient with ataxia, found along with a second INPP5E variant of uncertain significance, phase unknown (Sangermano et al. 2021. PubMed ID: 34188062; Benkirane et al. 2021. PubMed ID: 34234304). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.